Laboratoire de Pharmacologie-INSERM U1045, UFR des Sciences Pharmaceutiques, Université Bordeaux Segalen, Case 83, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France.
Ther Adv Respir Dis. 2013 Jun;7(3):175-200. doi: 10.1177/1753465812472940. Epub 2013 Jan 17.
Pulmonary hypertension (PH) is characterized by a progressive elevation of pulmonary arterial pressure due to alterations of both pulmonary vascular structure and function. This disease is rare but life-threatening, leading to the development of right heart failure. Current PH treatments, designed to target altered pulmonary vascular reactivity, include vasodilating prostanoids, phosphodiesterase-5 inhibitors and endothelin-1 receptor antagonists. Although managing to slow the progression of the disease, these molecules still do not cure PH. More effective treatments need to be developed, and novel therapeutic strategies, targeting in particular vascular remodelling, are currently under investigation. Reactive oxygen species (ROS) are important physiological messengers in vascular cells. In addition to atherosclerosis and other systemic vascular diseases, emerging evidence also support a role of ROS in PH pathogenesis. ROS production is increased in animal models of PH, associated with NADPH oxidases increased expression, in particular of several Nox enzymes thought to be the major source of ROS in the pulmonary vasculature. These increases have also been observed in vitro and in vivo in humans. Moreover, several studies have shown either the deleterious effect of agents promoting ROS generation on pulmonary vasculature or, conversely, the beneficial effect of antioxidant agents in animal models of PH. In these studies, ROS production has been directly linked to pulmonary vascular remodelling, endothelial dysfunction, altered vasoconstrictive responses, inflammation and modifications of the extracellular matrix, all important features of PH pathophysiology. Altogether, these findings indicate that ROS are interesting therapeutic targets in PH. Blockade of ROS-dependent signalling pathways, or disruption of sources of ROS in the pulmonary vasculature, targeting in particular Nox enzymes, represent promising new therapeutic strategies in this disease.
肺动脉高压（PH）的特征是由于肺血管结构和功能的改变导致肺动脉压逐渐升高。这种疾病虽然罕见，但却有生命危险，会导致右心衰竭。目前的 PH 治疗方法旨在针对改变的肺血管反应性，包括血管扩张性前列腺素、磷酸二酯酶-5 抑制剂和内皮素-1 受体拮抗剂。尽管这些方法能够减缓疾病的进展，但它们仍然不能治愈 PH。需要开发更有效的治疗方法，目前正在研究针对血管重塑的新治疗策略。活性氧（ROS）是血管细胞中重要的生理信使。除了动脉粥样硬化和其他系统性血管疾病外，新的证据还支持 ROS 在 PH 发病机制中的作用。PH 动物模型中 ROS 的产生增加，与 NADPH 氧化酶表达增加有关，特别是几种 Nox 酶，这些酶被认为是肺血管中 ROS 的主要来源。这些增加在体外和体内的人类中也观察到了。此外，几项研究表明，促进 ROS 生成的药物对肺血管的有害作用，或者相反，抗氧化剂在 PH 动物模型中的有益作用。在这些研究中，ROS 的产生与肺血管重塑、内皮功能障碍、血管收缩反应改变、炎症和细胞外基质的改变直接相关，这些都是 PH 病理生理学的重要特征。总的来说，这些发现表明 ROS 是 PH 治疗的一个有趣的靶点。阻断 ROS 依赖的信号通路，或破坏肺血管中的 ROS 来源，特别是针对 Nox 酶，是这种疾病的一种有前途的新治疗策略。
